This project is designed to identify the molecular events involved in the regulation of human globin gene expression. In particular, we are utilizing the thalassemias as model systems. Nondeletion Hb H disease results from disordered regulation of alpha gene expression. In this condition, the alpha genes remain intact but are not expressed efficiently. We are studying populations known to harbor alpha-thalassemia. We have tentatively identified Arab North Africa as a region where nondeletion alpha thalassemia may be common and therefore may serve as a resource for molecular studies. As part of this population study we have generated data from analysis of the sickle gene - Hpa 1 linkage suggesting that at least two separate sickle gene mutations arose within West Africa. The laboratory is now engaged in continuing studies of alpha thalassemia and the sickle gene by gene mapping studies from various populations. In addition, we are beginning cloning and isolation experiments to study alpha gene loci from one patient with nondeletion Hb H disease. Finally, we are establishing conditions for studying transcriptional controls at the level of chromatin.